The present invention relates to a process for manufacturing an adsorbent for the purpose of reducing the concentration of fibrinogen and/or fibrin in blood or blood plasma, in which a carrier material is activated by the introduction of covalently bonded alkaline groups, and the activated carrier material then undergoes a thermal treatment at a temperature of over 100xc2x0 C. Furthermore, the invention relates to an adsorbent manufactured in this way, and a method of producing an adsorber from the adsorbent for the purpose of reducing the concentration of fibrinogen and/or fibrin in blood or blood plasma.
Adsorbents are widespread in medical technology. Adsorbers with adsorbents that remove low density lipoproteins (LDL) from blood or reduce their concentration, such as those known from German Patent No. 39 32 971, are frequently described. German Patent No. 39 32 971 describes the adsorber material as an organic carrier having a fixed particle size and exclusionary threshold, which bears a ligand on its surface, to which the LDL molecule bonds.
In German Patent No. 197 29 591, the use of a ligand for fibrinogen and/or fibrin is claimed in order to cure the diseases engendered on the basis of an excessively elevated proportion of fibrinogen in the blood, or to at least prevent such diseases. In the process described in German Patent No. 197 29 591, the ligand is defined as a substance that binds specifically to fibrinogen and/or fibrin, and is preferably a peptide with three to ten amino acids.
The reduction of concentrations of plasma fibrinogen, immunoglobulin G (IgG) and immunoglobulin M (IgM) by means of immunoadsorption therapy with tryptophan or phenylalanine adsorbents is known from Artificial Organs, volume 20, No. 9 (1996), pp. 986-990. In immunoadsorption therapy, adsorption columns are used which exhibit spherical polyvinyl alcohol (PVA) gel particles as carriers. On their surfaces, the PVA gel particles carry either tryptophan or phenylalanine as an amino acid ligand, which is covalently bonded to the PVA by way of spacers. The plasma, which is separated from blood cells, is conducted via the adsorption column and thereafter, before being led back to the patient, reunited with the blood cells again. With this immunoadsorption therapy, simultaneously, the concentrations of fibrinogen, IgG and IgM are significantly reduced.
Even if adsorption has, in the meantime, made its way into the clinical routine as a means of ameliorating illnesses, increasing demands are being made on the selectivity of adsorption. In other words, although the adsorbers are not permitted to adsorb any proteins that are needed by human beings, or as few of them as possible, it is also desirable that the reduction of the concentration of harmful proteins be so great that the extra-corporal treatment, which is a burden to the patient, is as effective as possible.
It has been known for some time that a number of diseases are based upon a lack of micro-circulation of the blood. The diseases enumerated in Table 1, which follows below, could be mentioned by way of example.
Thus far, these diseases have, for the most part, been treated with medications, and often, in the process, nothing more than an elimination of the symptoms has occurred. The measures that have been known thus far for treating and influencing the micro-circulation and the rheology of the blood consist of plasma exchange, heparin-induced extra-corporal LDL cholesterol precipitation (HELP) and the adsorption of fibrinogen with the aid of a ligand, to which fibrin and/or fibrinogen specifically binds. The use of a ligand of that type is described in German Patent No. 197 29 591. Peptides that exhibit, preferably, three to ten amino acids, such that the particularly preferred sequence is said to be glycine-proline-arginine-proline-X, are cited as ligands.
The synthetic production of peptides, however, is a complex and costly process, so that the use of a specific adsorber as a ligand is very costly.
Beyond that, peptides longer than a certain length trigger antibody reactions so that after repeated use, pronounced immune reactions can result in the long term. Indeed, in order to reduce the immune defense, peptide oligomers that are as short as possible are used, but immunogenicity can never be fully precluded. In addition, leakage, an unnoticed release of pieces of peptide, is particularly dangerous, because as components of the body""s inherent structures, peptides represent bioactive molecules.
In addition, as described in Artificial Organs, volume 20, No. 9 (1996), pp. 986-990, immunoadsorption therapy also employs the amino acids tryptophan or phenylalanine for bonding onto the PVA gel particles, and therefore, it too is complicated and costly. Furthermore, with this therapy, even substances that should not be removed from the plasma, such as IgG and IgM, are removed from the plasma in amounts that are comparable to those of the fibrinogen.
The object of the present invention is to create a process for manufacturing an adsorbent for the purpose of reducing the concentration of fibrinogen and/or fibrin in blood or blood plasma that exhibits better elimination ratios and can be produced more cost-effectively than those adsorbents known in the art. The adsorbent should also be bio-compatible and cause no immune defense.